Catalytic Asymmetric Synthesis of 3‐(α‐Hydroxy‐β‐carbonyl) Oxindoles by a ScIII‐Catalyzed Direct Aldol‐Type Reaction

A direct catalytic asymmetric aldol‐type reaction of 3‐substituted‐2‐oxindoles with glyoxal derivatives and ethyl trifluoropyruvate, catalyzed by a chiral N,N′‐dioxide–Sc(OTf)₃ (Tf=trifluoromethanesulfonyl) complex, has been developed that tolerates a wide range of substrates. The reaction proceeds in good yields and excellent enantioselectivities (up to 93 % yield, 99:1 diastereomeric ratio (dr), and >99 % enantiomeric excess (ee)) under mild conditions, to deliver 3‐(α‐hydroxy‐β‐carbonyl) oxindoles with vicinal quaternary–tertiary or quaternary–quaternary stereocenters. Even with 1 mol % catalyst loading or on scaleup (10 mmol of starting material), maintenance of ee was observed, which showed the potential value of the catalyst system. In studies probing the reaction mechanism, a positive nonlinear effect was observed and Sc^III‐based enolate intermediates were detected by using ESIMS. On the basis of the experimental results and previous reports, a possible catalytic cycle was assumed.     

A Metal‐free Approach to 3‐Aryl‐3‐hydroxy‐2‐oxindoles by Treatment of 3‐Acyloxy‐2‐oxindoles with Diaryliodonium Salts

A mild, metal‐free approach has been realized for the facile construction of highly valuable 3‐(hetero)aryl‐3‐hydroxy‐2‐oxindoles. Direct arylations of 3‐acyloxy‐2‐oxindoles with diaryliodonium salts as arylation reagents are implemented in the presence of K₂CO₃ at room temperature without using an organometallic promoter to deliver an array of 3‐(hetero)aryl‐3‐hydroxy‐2‐oxindoles in good yields.     

Preparation of Furo[3,2‐c]coumarins from 3‐Cinnamoyl‐4‐hydroxy‐2H‐chromen‐2‐ones and Acyl Chlorides: A Bu3P‐Mediated C‐Acylation/Cyclization Sequence

A Bu₃P‐mediated cyclization reaction of 3‐cinnamoyl‐4‐hydroxy‐2H‐chromen‐2‐ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2‐c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl‐substituted furo[3,2‐c]coumarins by the treatment with carbonyl electrophiles under basic conditions.     

Preparation of 2‐phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline and 2‐methyl‐4‐oxo‐3,4‐dihydroquinazoline derivatives formation

The cyclization of phenacyl anthranilate has been studied with the aim to develop the synthesis of 2‐(2′‐aminophenyl)‐4‐phenyloxazole. However, a different course of the reaction than expected was observed. 2‐Phenyl‐2‐hydroxymethyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 3a ) was formed by the reaction of phenacyl anthranilate ( 2 ) with ammonium acetate under various conditions. 3‐Hydroxy‐2‐phenyl‐4(1H)‐quinolinone ( 4 ) arose by heating compound 3a in acetic acid. The same compound was obtained by melting compound 3a , but the yield was lower. Different types of products resulted in the reaction of compound 3a with acetic anhydride. Under mild conditions acetylated products 2‐acetoxymethyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 7a ) and 2‐acetoxymethyl‐3‐acetyl‐2‐phenyl‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline ( 8 ) were prepared. If the reaction was carried out under reflux of the reaction mixture, molecular rearrangement took place to give cis and trans 2‐methyl‐4‐oxo‐3‐(1‐phenyl‐2‐acetoxy)vinyl‐3,4‐dihydroquinazolines ( 9a and 9b ). All prepared compounds have been characterised by their ¹H, ¹³C and ¹⁵N NMR spectra, IR spectra and MS.     

Synthesis of C3‐Fluorinated Oxindoles through Reagent‐Free Cross‐Dehydrogenative Coupling

Reported herein is an unprecedented synthesis of C3‐fluorinated oxindoles through cross‐dehydrogenative coupling of C(sp³)‐H and C(sp²)‐H bonds from malonate amides. Under the unique and mild electrochemical conditions, the requisite oxidant and base are generated in a continuous fashion, allowing the formation of the base‐ and heat‐sensitive 3‐fluorooxindoles in high efficiency with broad substrate scope. The synthetic usefulness of the electrochemical method is further highlighted by its easy scalability and the diverse transformations of the electrolysis product.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

Enantioselective Cascade Michael Addition/Cyclization Reactions of 3‐Nitro‐2H‐Chromenes with 3‐Isothiocyanato Oxindoles: Efficient Synthesis of Functionalized Polycyclic Spirooxindoles

An unprecedented Zn(OTf)₂‐catalyzed asymmetric Michael addition/cyclization cascade of 3‐nitro‐2H‐chromenes with 3‐isothiocyanato oxindoles has been disclosed. This transformation provides an efficient access to various synthetically important polycyclic spirooxindoles in a highly stereoselective manner under mild conditions (72–99 % yields, up to >95:5 d.r. and >99 % ee). The reaction leads to the formation of three consecutive stereocenters, including 1,3‐nonadjacent tetrasubstituted carbon stereocenters, in a single operation. A bifunctional activation model of the chiral Zn(OTf)₂/bis(oxazoline) complex was proposed based on control experiments, wherein the Zn^II moiety serves as a Lewis acid and the N atom of the free NH group acts as a Lewis base by a hydrogen‐bonding interaction.     

Organocatalytic Asymmetric Conjugate Addition of 3‐Monosubstituted Oxindoles to (E)‐1,4‐Diaryl‐2‐buten‐1,4‐diones: A Strategy for the Indirect Enantioselective Furanylation and Pyrrolylation of 3‐Alkyloxindoles

An asymmetric conjugate addition of 3‐monosubstituted oxindoles to a range of (E)‐1,4‐diaryl‐2‐buten‐1,4‐diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3′‐disubstituted oxindoles that contain a 1,4‐dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high‐to‐excellent yields (up to 98 %), with excellent diastereomeric and moderate‐to‐high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4‐dicarbonyl moiety in the resultant Michael adducts under different Paal–Knorr conditions results in two new kinds of 3,3′‐disubstituted oxindoles—3‐furanyl‐ and 3‐pyrrolyl‐3‐alkyl‐oxindoles—in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two‐step strategy of sequential conjugate addition/Paal–Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3‐alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3′‐disubstituted oxindole derivatives.     

A New Cyclization/Decarboxylation Reaction of Isatins with Acyl Chlorides for the Facile Synthesis of 3‐Alkenyl‐Oxindoles

The first cyclization/decarboxylation reaction of isatins with acyl chlorides promoted by 4‐dimethylaminopyridine (DMAP) was described and a series of desired 3‐alkenyl‐oxindoles were obtained in good yields (up to 80%) and E/Z selectivities (up to 6.4/1). This protocol provided a new and feasible access to 3‐alkenyl‐oxindoles.     

Highly Stereoselective Conjugate Addition and α‐Alkynylation Reaction with Electron‐Deficient Alkynes Catalyzed by Chiral Scandium(III) Complexes

The highly Z‐selective asymmetric conjugate addition of 3‐substituted oxindoles to alkynyl carbonyl compounds has been developed by using scandium complexes of chiral N,N′‐dioxides under mild conditions. The thermodynamically unstable Z‐olefin derivatives were obtained in excellent yields and high enantiomeric and geometric control. The catalyst was also found to be effective in the asymmetric acetylenic substitution reaction of 3‐substituted oxindoles, giving excellent enantioselectivities.     

Synthesis of α‐Aryl Esters and Nitriles: Deaminative Coupling of α‐Aminoesters and α‐Aminoacetonitriles with Arylboronic Acids

Transition‐metal‐free synthesis of α‐aryl esters and nitriles using arylboronic acids with α‐aminoesters and α‐aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp³)? N bonds into C(sp³)? C(sp²) bonds. The reaction conditions are mild, demonstrate good functional‐group tolerance, and can be scaled up.     

A Highly Efficient Friedel–Crafts Reaction of 3‐Hydroxyoxindoles and Aromatic Compounds to 3,3‐Diaryl and 3‐Alkyl‐3‐aryloxindoles Catalyzed by Hg(ClO4)2⋅3 H2O

We report a highly efficient Friedel–Crafts reaction of 3‐alkyl or 3‐aryl 3‐hydroxyoxindoles with a variety of aromatic and heteroaromatic compounds to unsymmetrical 3,3‐diaryloxindoles or 3‐alkyl‐3‐aryloxindoles, which are interesting medicinal targets and useful building blocks for the synthesis of natural products. Hg(ClO₄)₂ ? 3 H₂O was identified as a powerful catalyst for this reaction, and is significantly more efficient than other screened metal perchlorate hydrates and Brønsted acids such as HOTf and HClO₄. The high catalytic property of Hg(ClO₄)₂ ? 3 H₂O originates from the unprecedented dual activation effects of aromatic mercuration, which could generate a strong protic acid to facilitate the generation of a carbocation at the C3‐position of oxindoles and simultaneously form the more reactive nucleophilic reaction partner.     

One‐Pot Synthesis of 4‐(2,3‐Dihydro‐2‐hydroxy‐1,3‐dioxo‐1H‐inden‐2‐yl)‐Substituted 1‐Aryl‐1H‐pyrazole‐3‐carboxylates via a Tandem Three‐Component Reaction

The hitherto unreported, highly functionalized 1H‐pyrazole‐3‐carboxylates 3 have been synthesized in good yields via a one‐pot three‐component domino reaction of phenylhydrazines, dialkyl acetylenedicarboxylates, and ninhydrin under mild conditions for the first time. No co‐catalyst or activator is required for this multicomponent reaction, and the reaction is, from an experimental point of view, simple to perform (Scheme 1). The structures of compounds 3 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization/addition reaction is proposed (Scheme 2).     

Cycloaromatization Reaction of 4‐Alkoxy‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐Diaminotoluene: The Unexpected Regioselective Synthesis of 2,4,7,8‐Tetrasubstituted Quinolines

This article reports a convenient and general method for the regioselective synthesis of a new series of 2‐alkyl(aryl)‐8‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines in 86–93% yields, from cycloaromatization reactions of N‐(oxotrifluoroalkenyl)‐2,6‐diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4‐alkoxy‐4‐alkyl(aryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones [CF₃C(O)CH═C(R)OR¹, where R = H, Me, Ph, 4‐FPh, 4‐BrPh, 4‐MePh, and R¹ = Me, Et] with 2,6‐diaminotoluene (2,6‐DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2‐aryl(heteroaryl)‐4‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines from direct cyclocondensation reactions of 4‐alkoxy‐4‐aryl(heteroaryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐diaminotoluene in methanol under mild conditions, in 21–36% yields.     

An Efficient One‐pot Three‐component Method for the Synthesis of 5‐Amino‐3‐(2‐oxo‐2H‐chromen‐3‐yl)‐7‐aryl‐7H‐thiazolo[3,2‐a]pyridine‐6,8‐dicarbonitriles

A facile, convenient, and adequate method has been developed for the synthesis of novel 5‐amino‐3‐(2‐oxo‐2H‐chromen‐3‐yl)‐7‐aryl‐7H‐thiazolo[3,2‐a]pyridine‐6,8‐dicarbonitriles ( 6 ) by employing 2‐(4‐(2‐oxo‐2H‐chromen‐3‐yl)thiazol‐2‐yl)acetonitrile ( 3 ) as an important precursor. Initially, we have synthesized the target compounds in a stepwise manner and then approached a tandem method to examine the feasibility of one‐pot method. Subsequently, one‐pot three‐component protocol has been established for the synthesis of title compounds by the reaction of 3 with benzaldehyde and malononitrile in refluxing ethanol engender a new six‐membered thiazolo[3,2‐a] pyridine as a hybrid scaffold. Reaction conditions were optimized for this reaction and a broad substrate scope with various aryl and heteroaryl aldehydes make this protocol very practical, attractive, and worthy. Mechanistic aspects for the formation of these compounds were outlined comprehensively. Characterization of these newly synthesized compounds was achieved by means of IR, ¹H NMR, ¹³C NMR, and HRMS.     

Pictet‐spengler synthesis of pyrazole‐fused β‐carbolines

The synthesis of new pyrazolo[4,3‐c]β‐carbolines ( 8a,b ) is achieved by condensation of the appropriate aldehyde with 3‐(4‐amino‐1,3‐dimethylpyrazol‐5‐yl)indole ( 4 ) under Pictet‐Spengler reaction conditions. Regioselective cyclization occurred at the usual indole C‐2 position as evidenced from the ¹H‐and ¹³C nmr spectra of 8a,b which lack the pyrrolic H‐2 signal, present in 4 (δ 7.26, 1H, d, J_ch‐NH = 2‐5 Hz).     

Synthesis of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines from β‐alkoxy‐α,β‐unsaturated trihalomethyl ketones

The synthesis of a novel series of twelve 4‐(trihalomethyl)dipyrimidin‐2‐ylamines, from the cyclo‐condensation reaction of 4‐(trichloromethyl)‐2‐guanidinopyrimidine, with β‐alkoxyvinyl trihalomethyl ketones, of general formula: X₃C‐C(O)‐C(R²)=C(R¹)‐OR, where: X = F, Cl; R = Me, Et, ‐(CH₂)₂‐, ‐(CH₂)₃‐; R¹ = H, Me; R² = H, Me, ‐(CH₂)₂‐, ‐(CH₂)₃‐, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin‐2‐ylamines in 65‐90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines was studied in detail by ¹H‐, ¹³C‐ and 2D‐nmr spectroscopy.     

Synthesis and Cyclization of 8‐Formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic Acids

A facile synthesis of a series of new quinoline‐8‐carbaldehyde compounds, namely 8‐formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic acids ( 4a – 4h ) and 13‐oxo‐6,13‐dihydro[1]benzoxepino[3,4‐b]quinoline‐8‐carbaldehyde ( 5a – 5g ) is described, involving the one‐pot synthesis reaction of ethyl 2‐(chloromethyl)‐8‐formylquinoline‐3‐carboxylate ( 3 ) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline‐8‐carbaldehydes 4a – 4h and 5a – 5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.     

An Efficient Synthesis of N‐Substituted‐3‐aryl‐3‐(4‐hydroxy‐6‐methyl‐2‐oxo‐2H‐pyran‐3‐yl)propanamides by Four‐Component Reaction in Aqueous Medium

A mild and efficient synthesis of N‐substituted‐3‐aryl‐3‐(4‐hydroxy‐6‐methyl‐2‐oxo‐2H‐pyran‐3‐yl)propanamides via four‐component reaction of an aldehyde, amine, Meldrum's acid, and 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one in the presence of benzyltriethylammonium chloride (TEBAC) in aqueous medium is described. This method has the advantages of accessible starting materials, good yields, mild reaction conditions, and begin environmentally friendly.     

Construction of Spirocyclic Oxindoles through Regio‐ and Stereoselective [3+2] or [3+2]/[4+2] Cascade Reaction of α,β‐Unsaturated Imines with 3‐Isothiocyanato Oxindole

On the basis of asymmetric regioselective [3+2] or [3+2]/[4+2] cascade reaction of 3‐isothiocyanato oxindoles with C=C and C=N bonds of α,β‐unsaturated methanesulfonamides, diversified S‐containing heterocyclic spirooxindole derivatives could be obtained in high yields along with good to excellent diastereo‐ and enantioselectivities under mild conditions in the presence of cinchona alkaloid‐derived organocatalysts.